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Lesion level-dependent glucocorticoid dysregulation exacerbates systemic muscle wasting during the acute phase of paraplegic rodent spinal cord injury

Harrigan, Markus E
http://orcid.org/0000-0002-3809-1951
http://rave.ohiolink.edu/etdc/view?acc_num=osu1650391916848736

Abstract Details

2022, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Recently an increased appreciation for the systemic consequences of spinal cord injury (SCI) has re-emerged. These pathophysiological processes provide novel therapeutic targets, beyond central nervous system (CNS) regeneration, to improve clinical outcomes. This includes muscle wasting, an endemic consequence of SCI. Muscle tissue, even when not actively participating in movement of a limb, hosts additional crucial functions for SCI patients beginning already immediately after injury, as the loss of muscle tissue contributes to mortality, impaired functional recovery and the development of additional secondary complications. A deeper understanding of muscle pathophysiology early after SCI is necessary since current interventions are minimally effective and are not started until after considerable muscle wasting has already occurred. SCI disrupts connectivity between the nervous system and muscles, resulting in paralysis of muscles at and below the injury lesion level. Though denervation and inactivity of paralyzed muscles are common explanations for localized sublesional muscle atrophy, they cannot explain the rapid systemic wasting of non-paralyzed muscles retaining fully intact motor innervation from spinal cord levels rostral to the SCI lesion. Therefore, unidentified systemic mechanisms of muscle wasting present novel therapeutic targets to rescue muscle tissue during the critical acute period ‘bridging’ between SCI and rehabilitation. To investigate systemic mechanism originating in the spinal cord we evaluated muscle after rodent SCI at two different thoracic levels. Both high and low thoracic SCI retain full forelimb innervation, but muscle wasting was further exacerbated by high thoracic SCI. Concurrently, high, compared to low, thoracic SCI exacerbates acute hypercortisolism. Accordingly, we hypothesized that glucocorticoid excess, by means of a putative SCI level-dependent hypercortisolism mechanism, represents a candidate catabolic signal exacerbating systemic muscle wasting after high thoracic SCI. Through gene expression and protein analyses, we identified distinctive characteristics of glucocorticoid-mediated muscle wasting early after high thoracic SCI. By plasma protein and adrenal histological analyses, during acute and chronic high thoracic SCI we delineated dynamic hypercortisolism resulting from aberrant adrenal dysfunction disintegrating from hypothalamic-pituitary-adrenal (HPA)-axis control and concurrent glucocorticoid regulatory protein deficiency. Lastly, in vivo anti-glucocorticoid interventions combatting neuroendocrine dysfunction (glucocorticoid receptor antagonism, adrenalectomy, skeletal muscle glucocorticoid receptor knockout) protecting muscle glucocorticoid receptors from glucocorticoid excess rescues muscle tissue systemically and ablates the SCI level-dependent severity of acute muscle wasting. In conclusion, our findings indicate the presence of lesion level-dependent systemic muscle wasting during the acute phase of SCI, which is mediated by adrenal glucocorticoid excess and dysregulation, and imply that therapeutic normalization of the glucocorticoid imbalance in SCI patients could be a strategy to prevent detrimental muscle wasting.
Jan Schwab (Advisor)
Andrea Tedeschi (Committee Member)
Phillip Popovich (Committee Member)
William Arnold (Committee Member)
Harold Fisk (Other)
178 p.
Biomedical Research; Endocrinology; Experiments; Health; Health Sciences; Medicine; Neurobiology; Neurosciences; Rehabilitation
spinal cord injury; SCI; muscle; skeletal muscle; muscle wasting; neuroendocrine; endocrine; adrenal gland; glucocorticoid; acute; systemic; adrenalectomy; glucocorticoid receptor

Recommended Citations

Citations

  • Harrigan, M. E. (2022). Lesion level-dependent glucocorticoid dysregulation exacerbates systemic muscle wasting during the acute phase of paraplegic rodent spinal cord injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650391916848736

    APA Style (7th edition)

  • Harrigan, Markus. Lesion level-dependent glucocorticoid dysregulation exacerbates systemic muscle wasting during the acute phase of paraplegic rodent spinal cord injury. 2022. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1650391916848736.

    MLA Style (8th edition)

  • Harrigan, Markus. "Lesion level-dependent glucocorticoid dysregulation exacerbates systemic muscle wasting during the acute phase of paraplegic rodent spinal cord injury." Doctoral dissertation, Ohio State University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=osu1650391916848736

    Chicago Manual of Style (17th edition)

osu1650391916848736
© 2022, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.